an autodidact meets a dilettante…

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Archive for the ‘cytokines’ Category

stuff about Covid-19: cytokine problems

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got all that?

Canto: So what are cytokines? They’re ‘signalling proteins, usually less than 80kDa in size’ – that means kilodaltons, and it refers to molecular mass. Proteins have a huge variety of shapes and sizes, the largest being titin, with a mass of 3,816,188.13 Da. I don’t know why they don’t keep to kilodaltons. I presume the daltons measurement is in memory of the pioneering British chemist John Dalton, a truly inspiring character. Cytokines are quite small proteins, I think. Or peptides, which are described on other science sites as not being proteins, or not quite, which is confusing.

Jacinta: We’re looking at a ScienceDirect website which is pretty technical, but it says cytokines regulate many biological functions including those related to innate and acquired immunity. Here’s its ‘operational definition’:

Cytokines can be defined operationally as polypeptides secreted by leukocytes and other cells that act principally on hematopoietic cells, the effects of which include modulation of immune and inflammatory responses.

So peptides are short strings of amino acids, and proteins are longer strings of amino acids, so polypeptides are apparently more than just peptides but not quite proteins. Very weird. Leukocytes are white blood cells, of which there are three main types (I think): monocytes, lymphocytes (T cells and B cells) and granulocytes (neutrophils, eosinophils and basophils). Leukocytes are made in our bone marrow and are found in our blood and lymph. I’d love to learn about lymph one day.

Canto: So leukocytes are part of our immune system, as are the cytokines they secrete. Hematopoietic cells – always worth breaking things down: hema, or haema, always refers to blood, and poiesis, from ancient Greek, essentially means production or bringing into being. Presumably, then, these hematopoietic cells exist in the bone marrow, where they produce leukocytes. And yet… that all seems to mean that cytokines are secreted (and presumably produced) by leukocytes to act on hematopoietic cells that produce leukocytes… It seems a bit circular to me.

Jacinta: Certainly complex. Let’s barge on. The ScienceDirect site has it that cytokines are secreted by many cell types, often at high concentrations, and are mostly involved in cell-to-cell interactions with neighbouring cells. This is called paracrine signalling, as opposed to other forms of signalling (endocrine, juxtacrine and autocrine). However, cytokines can sometimes use those other forms. There are many different groups of cytokines, usually named for their most significant effects, as we see them, but they’re actually pleiotropic, meaning they have each a variety of functions, and those functions can be mediated by other cytokine groups. So, certainly complex, but in terms of their function in response to airways diseases…

Canto: But now I’m hearing that Covid-19 isn’t necessarily an airways disease, or only an airways disease. It may affect the brain and the nervous system, the kidneys, the heart, the blood…

Jacinta: Hmmm, so much more to explore, before we all die. But knowledge is power, the more we know, the more we can defend ourselves. Let’s all be Popperian optimists and rise to the challenge. Here’s an overview, from a 2009 article on cytokines as related to asthma and COPD:

The major classes of cytokines include: pro- and anti-inflammatory cytokines, cytokines of neutrophil and eosinophil recruitment and activation, cytokines derived from T-helper (Th) and T-regulatory (Tregs) cells, and cytokines of T-cell recruitment and growth factors.

The cells mentioned are all leukocytes. But the storm of cytokines may well be causative of those other symptoms found in Covid-19 sufferers, such as blood clots. A very recent article in the Lancet has this to say in reference to what we’re seeing:

the overproduction of early response proinflammatory cytokines (tumour necrosis factor [TNF], IL-6, and IL-1β) results in what has been described as a cytokine storm, leading to an increased risk of vascular hyperpermeability, multiorgan failure, and eventually death when the high cytokine concentrations are unabated over time. Therefore, therapeutic strategies under investigation are targeting the overactive cytokine response with anticytokine therapies or immunomodulators, but this must be balanced with maintaining an adequate inflammatory response for pathogen clearance.

Canto: Wow, I suppose one thing we’ll be learning fast from this pandemic will be a lot more about cytokine production and how it can be abated without risk to the immune system. I wonder if there are any ‘anticytokine therapies’ at present?

Jacinta: Well I’ve read this Lancet article and I can’t pretend to comprehend all that’s in it, but of course it tries to address all we’re concerned about here so I’m going to try to explain it in my way. Hospitalised Covid-19 patients are presenting with pneumonia, ARDS and other respiratory conditions, and sepsis. Sepsis is a broad term, referring to an unbalanced blood immune response which, at its worst, can lead to multiple organ failure. Vascular hyperpermeability, mentioned above, is defined as ‘the excessive leakage of fluid and proteins from blood vessels to the interstitial space‘, being the fluid-filled space around tissue cells. The protease thrombin, which is apparently a coagulant (among other things) and not itself a cytokine, is in normal circumstances tightly regulated in the body by multiple factors, all of which can be impaired by hyperinflammatory conditions. The procoagulant-anticoagulant balance is disrupted, which can lead to microthrombosis and ‘disseminated intravascular coagulation’. Which I think is self-explanatory, and not good. The article refers to ‘raised d-dimer concentrations’ which has to do with fibrin, a fibrous protein involved in blood-clotting. The difficulty is that treatment with ‘endogenous anticoagulants’ has its dangers, shown in previous negative trials. There’s this important factor in respiratory physiology called the ventilation/perfusion (V/Q) ratio, with V being the measure of air getting to the alveoli, and Q the measure of blood getting to the alveoli. A mismatch there can affect the possibility of venous thromboembolism – blood clots, to oversimplify. What this forbiddingly technical Lancet article is suggesting, finally, is that studies conducted on murine [rat/mouse] models of PAR-1 antagonists (PAR-1 being protease-activated receptor, the main thrombin receptor mediating platelet aggregation) have shown some promise, and need to be further investigated tout de suite. Here are the authors’ final words:

Targeting thrombin, coagulation factor Xa or PAR-1, might therefore be an attractive approach to reduce SARS-CoV-2 microthrombosis, lung injury, and associated poor outcomes.

References

https://en.wikipedia.org/wiki/John_Dalton

https://www.sciencedirect.com/topics/neuroscience/cytokines

https://www.medicalnewstoday.com/articles/326701

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/leukocyte

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30216-2/fulltext

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049450/

Written by stewart henderson

May 2, 2020 at 4:51 pm

Covid19: world progress, cytokine storms, our plans

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to be explored further

Canto: So while we need to be worried about – and to know something about – the cytokine storm that the Covid19 infection can lead to (and we’ll learn about that soon), there’s also a storm of activity on the SARS-CoV-2-fighting front.

Jacinta: Yes, intravenous zinc was talked about in the Medcram series as an effective tool in fighting viral pneumonia, and a world-first trial is being conducted by Austin Health and Melbourne University to test its effectiveness for Covid-19 sufferers with respiratory problems. We’re still catching up on the Medcram series, and update 52 talks of the drug ivermectin, already on the WHO list of essential medicines. The WHO website, incidentally, is promoting a ‘solidarity’ clinical trial for Covid-19 treatments, involving, singly or in combination, remdesivir, hydroxychloraquine, lopinavir, ritonavir and interferon beta-1a. So that gives some idea of the work that’s going on to fight symptoms and reduce the death rate.

Canto: And, you know, I’ve been feeling guilty about singling out the USA as the worst-case scenario all round. It’s not actually so. It’s not fair to look at total figures and point out that the USA tops the list for Covid19 fatalities, and draw calamitous conclusions. You have to take into account its much larger population compared, for example, to number two on the list, Spain. The US has suffered about 2.5 times the fatalities of Spain, but it has about 7 times the population. In fact, if you look at fatalities as a proportion of population, there are many countries worse off than the USA – namely Spain, Italy, France, the UK, Belgium (the worst hit), the Netherlands, Switzerland, Ireland and Sweden. All European countries, notably.

Jacinta: Yes and I’m sure they’ll all have their particular stories to tell about why this is happening to them, and will be wanting to learn lessons from Taiwan, Hong Kong, South Korea, and even our big faraway island, but I really want to look at solutions, in terms of eradicating the virus, or blocking it, or building up our immunity. Having said that, flattening the curve, and reducing fatalities, is a primary focus, which means continuing the physical distancing and looking for ways to keep economies running while this goes on. In spite of patches of civil libertarian activity here and there, the vast majority of our global population is on the same page with this, I think.

Canto: Well I’m looking at an Axios article from the Johns Hopkins website. It compares global performance under Covid19 to a mock pandemic exercise, Event 201, conducted some six months ago. They’ve found some positives and some negatives in their analysis. Positives – a greater degree of compliance with physical distancing measures than expected, ‘the degree of surge capacity augmentation in the health care system which has been possible’, and the rapid growth of international collaboration among scientists, leading to a quickened progress of trials for possible treatments. Negative – disparate and often contradictory messages from authorities – mostly political authorities – leading to confusion and distrust of governments and other institutions. This is partially explained by the complexity of the virus itself, which has made it difficult to characterise to the general public, and to be fully understood by non-medical authorities, such as political leaders.

Jacinta: It’s a weird situation, as there’s no end in sight, everyone’s worried about ending restrictions too soon, yet everyone’s worried about the economy, and those countries, like Australia, that are heading towards winter, are bracing for heightened problems, while northern hemisphere countries are hoping for summer’s relief but worried about the autumn when it might be hard to cope with a second outbreak, should it come. And medicos are warning that expectations of a vaccine in eighteen months might be overly optimistic. But I want to be optimistic – I want to look at anything that’ll reduce symptoms and save lives. One treatment, among many others it should be noted, is hydroxychloraquine, which is being given so much of a bad press, because of its being over-hyped by a Trump administration intent on getting political points for a silver-bullet cure. There have already been a number of small, less-than-gold-standard studies, some in which the drug is combined with the antibiotic azithromycin, and the results appear to be all over the place. We’re still awaiting the results of randomised, placebo-controlled, double-blinded studies, which are under way.

Canto: I note that a couple of reports on chloraquine and hydroxychloraquine on the JAMA website have been taken down, I suspect because of all the politicising. That’s a shame. Anyway I mentioned the cytokine storm at the beginning of this post, so I’ll try to comprehend it. A clue to the meaning comes in this mid-March article on the Lancet website. In an early sentence it mentions ‘cytokine storm syndrome’, and in the following sentence refers to the treatment of ‘hyperinflammation’. It seems the two terms are interchangeable. Another term, in the very next sentence, is ‘a fulminant and fatal hypercytokinaemia’….

Jacinta: Sounds like they’re just showing off.

Canto: Please don’t say that about our frontline covidtroops. Okay, a better site for understanding cytokines and their storms is this from New Scientist. As we’ve guessed, it’s an over-reaction of the immune system, sometimes fatal. Cytokines are small proteins, produced throughout the body, which trigger inflammation as an immune response. Sometimes the intensity of the cytokine response results in hyperinflammation. So you might say the cytokine storm is the cause and hyperinflammation the effect.

Jacinta: So this raises questions. For example, why do some have what seems an over-production of these cytokines and others don’t, in response to SARS-CoV-2 in particular? And what do these cytokines actually do to cause inflammation?

Canto: You’re asking me? Well, it’s conjectured that younger people don’t have the developed immune system that produces all these cytokines, and that’s why you don’t see symptoms. But that raises the question – do others have over-developed immune systems, but maybe only for this particular virus? Is there a general goldilocks level?

Jacinta: And is there a way of distinguishing between those who succumb to the hyperinflammation, which in turn can cause acute respiratory distress syndrome (ARDS), and those who succumb to the virus itself? Or is it always the immune response that does people in?

Canto: I don’t think so. If the immune response doesn’t work at all, I suspect the virus will spread like a cancer to the rest of the body?

Jacinta: That can’t be right. That’d mean those kids who don’t suffer the cytokine storm, or any immune reaction, would remain infected until it spread through their bodies and they dropped dead. That definitely isn’t happening.

Canto: No, you’re right – they’re developing antibodies, presumably, (and that’s a whole other story), without going through much in the way of suffering. In fact, children’s apparent immunity to the virus is something of a mystery that demands further research. If everyone could develop that kind of immunity…

Jacinta: So many questions we can’t answer. I mean, not just the myriad questions we, as dilettantes and autodidacts, can’t answer, but the fewer but many questions epidemiologists, virologists and ICU workers can’t answer. But I propose that we continue to try and educate ourselves and explore, in our feeble but earnest way. I propose that we dedicate this blog, for the foreseeable, to exploring terms and conditions, so to speak, and treatments, such as ‘cytokine’, ‘ACE-2’, ‘hypoxia’ and ‘quercetin’ and how they relate to or are affected by the Covid-19 infection. Like putting pieces together in a jigsaw puzzle, sort of. It might help us being overwhelmed by the whole picture.

Canto: Okay, let’s try it.

References

Coronavirus pandemic update 52, Medcram youtube video

https://coronavirus.jhu.edu/news

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext

https://www.newscientist.com/term/cytokine-storm/

https://www.centerforhealthsecurity.org/event201/

https://www.axios.com/coronavirus-global-pandemic-preparation-fdce4bff-f1d3-433d-bceb-cc20ac869102.html

https://jamanetwork.com/journals/jama/pages/coronavirus-alert

Written by stewart henderson

April 29, 2020 at 11:55 am